Dextran-alkyl methacrylate graft composition for contact lens and corneas

ABSTRACT

A dextran-alkyl methacrylate graft composition consisting essentially of a dextran unit of the formula (1) ##SPC1## 
     Wherein n is an integer of 5 to 150,000, and a poly(alkyl methacrylate) unit of the formula (2) ##EQU1## WHEREIN M IS AN INTEGER OF 50 TO 200,000 AND R is an alkyl group having 1 to 4 carbon atoms, 
     And a process for producing the same.

This is a continuation of application Ser. No. 376,183, filed July 3,1973 and now abandoned.

This invention relates to a novel water- and acetone-insolubledextran-alkyl methacrylate graft composition or graft copolymer capableof giving shaped articles having excellent shapability, surface wettingproperty and transparency.

More specifically, this invention relates to a dextranalkyl methacrylategraft composition consisting essentially of a dextran unit of thefollowing formula (1) ##SPC2##

Wherein n is an integer of 5 to 150,000, preferably 10 to 50,000,

And poly(alkyl methacrylate) unit of the following formula (2) ##STR1##WHEREIN M IS AN INTEGER OF 50 TO 200,000 AND R is an alkyl group having1 to 4 carbon atoms; and

To a process for preparing said composition.

A graft composition formed between acrylic acid or methacrylic acid andcellulose or starch of the type in which the constituent glucose unitsare bonded mainly at the 1-4 -position has been previously known.However, since shaped articles of the cellulose-methacrylic monomergraft composition are not satisfactory in wetting properties andtransparency, their utility is greatly restricted. Furthermore, shapedarticles of the starch-methacrylic monomer graft composition are brittleand have defects in strength and viscoelasticity. Aslo, they have poorwetting properties, and the utility of the composition is greatlyrestricted.

There was reported a graft composition of acrylic acid and a4-β-hydroxyethylsulfonyl-2-aminoanisole ether of a dextran of the typein which the constituent glucose units are bonded at the α-1-6-positionsuch as shown in formula (1), a graft composition of polyacryl hydrazideand the above dextran, and a graft composition of the above dextran andpolyacrylhydroxamic acid (A. D. Virmik, O. P. Laletina, M. A. Penenzhik,K. P. Khomiakov, Z. A. Rogovin, and G. Ya. Rosenberg, "High-MolecularCompounds", A. 10, 362 (1968 ). Since this graft composition iswater-soluble as is disclosed in the above report, its utility isextremely limited.

It has now been found that a novel dextranalkyl methacrylate graftcomposition composed of the units (1) and (2) described above can beproduced easily, and this composition can give shaped articles ofsuperior surface wetting properties and transparency, has superiorshapability suitable for use in such fields as contact lenses orartificial organs and superior water resistance and resistance to bodyliquids, and is free from interaction with living tissues. It has alsobeen found that the resulting composition has superior shapability shownby bending strength, the amount of flexure and Vicat softening point,tensile strength, surface wettability and transparency and is insolublein water and acetone.

Accordingly, an object of this invention is to provide a noveldextran-alkyl methacrylate graft composition.

Another object of this invention is to provide a process for producingthe above dextran composition.

Many other objects and advantages of this invention will become moreapparent from the following description.

The dextran-alkyl methacrylate graft composition of this inventionconsisting essentially of the dextran units of the above formulae (1)and (2) can be obtained by reacting dextran with an alkyl methacrylatehaving 1 to 4 carbon atoms in the alkyl group in the presence of a redoxcatalyst in the absence of molecular oxygen. This graft polymerizationreaction can be performed either in solution, emulsion or suspension. Apart or whole of the above redox catalyst may be replaced by a peroxidecatalyst or a diazo compound catalyst. If desired, the use of thecatalyst compound may be omitted, and the materials may be heatpolymerized under the suspending or emulsifying conditions. Or the useof the catalyst compound may be omitted, and ozone is introduced into anaqueous solution of dextran, after which the reaction system is heatedand the oxidized dextran is graft polymerized with an alkyl methacrylateunder the suspending or emulsifying conditions. Furthermore, it is alsopossible to polymerize the materials in solution by applying actinicradiation such as γrays, X-rays, electron rays or ultraviolet rays.Where graft polymerization is carried out using a redox catalyst,solution polymerization may be employed using a solvent which candissolve both the dextran and the alkyl methacrylate, such as dimethylformamide or dimethyl sulfoxide. Alternatively, the materials may bepolymerized in emulsion in the presence of a basic, neutral or acidicsurface active agent, preferably the neutral surfactant such as higheralkyl ethers of polyethylene glycol, in an aqueous medium. Or they maybe polymerized in suspension by omitting the use of surfactants. At thistime, the presence of molecular oxygen reduces the activity of the redoxcatalyst, and therefore, the reaction is desirably carried out afterpurging the liquid reaction medium and the reaction zone with nitrogen.The pH of the reaction system is not more than 6, preferably not morethan 3 under acidic conditions. It is not necessary to use a reducingcomponent conjointly with the redox catalyst used, and a tetravalentcerium compound or a pentavelent vanadium compound can be preferablyutilized as the redox catalyst. Examples of such a cerium compound arecerium ammonium nitrate, cerium sulfate, cerium ammonium sulfate, ceriumnitrate, and cerium ammonium pyrophosphate. Furthermore, a compoundcapable of forming the above compounds under acidic conditions duringthe polymerization reaction, such as ceriumhydroxide, can also be used.As the above vanadium compound, vanadic acid can be exemplified. Thereaction can be performed at room temperature, and temperatures within arange of 0° to 75° C. are generally employed.

When a peroxide catalyst or a diazo compound catalyst is used instead ofthe redox catalyst, the presence of molecular oxygen does not cause adisadvantage, and temperatures ranging from room temperature to 100° C.can be employed. Specific examples of these catalysts are peracids suchas hydrogen peroxide, persulfuric acid, peracetic acid or perbenzoicacid, alkylhydro- or dialkyl-peroxides with a C₁ -C₄ alkyl group such astertiary butyl hydroperoxide, methylhydroperoxide, diisopropyl peroxideor ditertiary butyl peroxide, and azo compounds such as benzenediazonium chloride, N-nitroso acetanilide or diazo thioether.

When actinic radiation is utilized, its application is carried out atroom temperature under conditions which ensure the intimate contact ofdextran with the alkyl methacrylate. Radiation can be applied to dextranprior to contact with the alkyl methacrylate.

When the catalyst is utilized, the concentrations of the dextran, alkylmethacrylate and catalyst based on the total volume of the reactionsystem can be varied freely. For example, the preferred dextranconcentration is 0.6 to 20 weight/volume %, the concentration of themethacrylate 1 to 30 weight/volume %, and the catalyst concentration 5.5× 10-3 to 11 × 10.sup.⁻¹ mol/liter.

Where the redox catalyst is used, it may be deactivated after reactionby using a deactivating agent such as hydroquinone, sodium sulfate orferrous sulfate. When graft polymerization is carried out using acatalyst, the reaction product is precipitated using an alcohol, and theresulting precipitate is treated with hot water to remove the unreacteddextran. The by-product polymethacrylate may be removed with a solventsuch as acetone, tetrahydrofuran, dimethyl formamide, ethyl acetate orchloroform.

Examples of the alkyl group of the alkyl methacrylate are methyl, ethyl,propyl and butyl, the methyl being especially preferred.

The ratio of the unit of formula (1) to the unit of formula (2) in thedextran/alkyl methacrylate graft composition can be freely chosen. Theratio of the formula (2) unit/formula (1) unit is preferably 50 to 3000% by weight.

The dextran-alkyl methacrylate graft composition of this invention isinsoluble in water and acetone at 25° C. In view of the fact thatdextran is soluble in water at 25° C. and poly (alkyl methacrylate) issoluble in acetone at 25° C., it is evident that the dextran-alkylmethacrylate graft composition of graft copolymer of this invention isnot a mixture of dextran and poly(alkyl methacrylate).

Furthermore, the dextran-alkyl methacrylate graft composition of thisinvention has a glass transition point and a softening initiation pointwhich are not possessed by dextran. This glass transition temperature isfar higher than that of poly (alkyl methacrylate).

For example, when a copolymer of dextran and methyl methacrylate shownin Example 1 to be given below is examined by differential thermalanalysis, it is seen that its glass transition point appears at 180° C.,and at about 275° C., a marked softening phenomenon (endothermicreaction) occurs.

On the other hand, differential thermal analysis of dextran having anintrinsic viscosity of 0.222 shows that it does not have a glasstransition point and a softening initiation point, but is merely heatdecomposed. Furthermore, differential thermal analysis of poly(methylmethacrylate) alone obtained by separating from the copolymer of Example1 shows that its glass transition point appears at 130° C., and itbegins to soften at 270° C.

The results of these analyses are shown in Table 1 below.

                  Table 1                                                         ______________________________________                                                     Glass transition                                                                         Softening initia-                                                  point (° C)                                                                       tion point (° C)                               ______________________________________                                        Copolymer of dextran                                                          and methyl methacrylate                                                                      180          275                                               Poly (methyl methacry-                                                        late)          130          270                                               Dextran        --           --                                                ______________________________________                                    

The infrared spectrum charts of the dextran-methyl methacrylate graftcomposition of this invention, dextran and poly (methyl methacrylate)are shown in FIG. 1. Line 1 refers to dextran, line 2 to poly (methylmethacrylate), and line 3 to the dextran-methyl methacrylate graftcomposition.

As is shown in FIG. 1, in the graft composition of this invention, anabsorption A₁ appears in the vicinity of 3410 cm.sup.⁻¹ whichcorresponds to an absorption A₃ ascribable to the stretching vibrationof --OH of the dextran, an absorption B₁ appears in the vicinity of 1725cm.sup.⁻¹ which corresponds to an absorption B₂ ascribable to thecarbonyl group >C=O of the polymethacrylate, and an absorption C₁appears in the vicinity of 1000 to 1150 cm.sup.⁻¹ which corresponds toan absorption C₃ ascribable to the pyranose ring of dextran.

Thus, the dextran-alkyl methacrylate graft composition of this inventionexhibits different solubility and thermal properties from dextran andpoly (alkylmethacrylate), and shows the above-described characteristicabsorptions in infrared absorption spectrum. From this fact, it isjudged that the graft composition of this invention is a novel compoundgraft polymerized in the same way as in a cellulose or starch and anacrylic monomer, and is not a mixture of dextran and poly(alkylmethacrylate).

The dextran-alkyl methacrylate graft composition of this invention ismelt-shapable, and may be in various forms such as powder, granules,pellets, flakes, filaments, films, sheets or tubes. Furthermore, theshaped articles made therefrom may be of such forms as can be used forvarious applications. For instance, the composition of this inventioncan be shaped into contact lenses to exhibit its excellent wettingproperties and transparency. Such contact lenses are well wettable withwater and tears, and have low water absorbability as in the conventionalcontact lens material [poly(methyl methacrylate) resin] and mechanicaland optical characteristics resembling those of the poly (methylmethacrylate) resin. Thus, this invention provides a contact lens whichmay be worn by persons who suffer from discomforts such as blood shoteyes, burning feelings in the eyes, and foggy views when provided withconventional contact lenses.

In the formation of the graft composition of this invention into acontact lens, the composition is placed in a mold and heated, and bypressing the mold using a press device, it is shaped into a sheet or rodform. The heating temperature employed at this time is preferably 170°to 230° C., and the pressure is preferably 50 to 150 Kg/cm². Preferably,the graft composition of this invention having a large grafting rate isshaped at a high temperature and a low pressure. Subsequently, withcontinued pressing, the mold is gradually cooled by passing cold water,and when the temperature of the mold falls below 50° C., the mold iswithdrawn from the press device and opened.

The shaped article so obtained is cut to a suitable size and thickness,and polished and processed on a bevel machine to form a contact lens.

Moreover, the graft composition of this invention can be fabricated intothe form of artificial organs such as artificial blood vessels,artificial bones, artificial kidneys, artificial corneas or false teeth,or components of these organs. Further, same as in the case of the knowncellulose-acrylic graft composition or starch-acrylic graft composition,the graft composition of this invention can be utilized as as excipientor carrier of pharmaceutically effective ingredients, a flocculatingagent (or precipitating agent), or an adhesive.

The shaping means can be freely chosen. For example, there can be used aheat and press molding method, a melt extrusion method, an injectionmolding method, or a casting method.

The following Examples together with Comparative Examples illustrate thepresent invention more specifically.

The various properties shown in these Examples and Comparative Exampleshave been examined by the following methods.

1. Grafting rate

The grafting rate is expressed by the following equation. ##EQU2##

2. Method of isolating poly(alkyl methacrylate) from the graftcomposition and the measurement of its degree of polymerization:

a. Method of isolation

The graft composition is heated at 30° C. for 2 hours in 72% H₂ SO₄.Water was added until the concentration of H₂ SO₄ becomes 2%, and thenit is boiled for 40 minutes. The solid is collected by filtration. It isthen dissolved in acetone, and filtered. Methanol is added to theresulting filtrate to form a precipitate. The precipitate is dried in avacuum drier held at 40° to 50° C.

b. Determination of the degree of polymerization

The poly (alkyl methacrylate) isolated and purified is dissolved in asolvent, and its intrinsic viscosity is measured using an Ostwaldviscometer. Its molecular weight is calculated by using the followingequation, and from the result, the degree of polymerization is computed.

    ______________________________________                                        (η)        = k.M                                                          (η)        intrinsic viscosity                                            M              molecular weight                                               k and α  constants as shown below                                       Poly(methyl methacrylate)                                                       k = 0.96 × 10.sup.-.sup.4                                               α = 0.69                                                                Solvent: acetone                                                              Temperature: 25° C.                                                  Poly(ethyl methacrylate)                                                        k = 0.283 × 10.sup.-.sup.4                                              α = 0.79                                                                Solvent: methyl ethyl ketone                                                  Temperature: 23° C.                                                  Poly (n-butyl methacrylate)                                                     k = 0.99 × 10.sup.4                                                     α = 0.67                                                                Solvent: dioxane                                                              Temperature: 25° C.                                                  Poly (isobutyl methacrylate)                                                    k = 0.861.sup.-.sup.4                                                         α = 0.70                                                                Solvent: methyl ethyl ketone                                                  Temperature: 25° C.                                                  ______________________________________                                    

From the molecular weight M obtained, the degree of polymerization [m informula (2)] is calculated on the basis of the following equation.

m=M/molecular weight of alkyl methacrylate monomer

3. Tensile strength, bending strength, contact angle, and waterabsorbtion:

a. Sample: a 1 mm thick sheet shaped by press at 200° C.

b. Tensile strength (Kg/cm²): A rectangular sample with a width of 12.7mm is used and the tensile strength is measured using an Autograph IM500. The test speed is 5 mm/min. and the testing temperature is 23° C.The interchuck distance is maintained at 50 mm.

c. Bending strength (Kg/mm²): Measured using an Autograph IM 500. Thesample used is of 3 cm width, 1 mm thickness and 10 cm length. Both endsin the longitudinal direction of the sample are supported on asupporting stand with a span of 5 cm. A load is exerted on the center ofthe sample, and the load (Pkg) at breakage or the maximum load ismeasured. The bending strength is calculated from the followingequation.

    Bending strength = 2.5 × P

d. Contact Angle: Using a contact angle meter (contact angle measuringapparatus produced by Kyowa Kagaku Company), a certain water drop (about0.02 ml.) is prepared by a microsyringe and is brought into contact withthe surface of the sample carefully. After 30 seconds from the contact,the water drop is photographed, and h and x shown in FIG. 2 aremeasured. The contact angle (θ) is calculated from the followingequation. The measuring temperature is 20° C.

    θ = 2 tan.sup.-.sup.1 h/x

e. Water absorbtion (%): A 25 × 7.5 mm sample is dried for 24 hours inair at 50° C., and then allowed to cool. After weighing, the sample isallowed to stand for 24 hours in distilled water at room temperature.The sample is then withdrawn from the water and wiped lightly with acloth, and its weight is measured. The water absorption is determinedfrom the difference in weights.

f. Vicat softening point: Using a needle penetrating softening pointtester, a steel needle (surface area 1 mm²) having a flat tip with adiameter of 1.13 mm is placed perpendicularly on the surface of a sample(surface area 1 cm², thickness 3 mm), and by exerting a load of 5 Kg onthis needle, the temperature is raised at a rate of 50° C. per hour in aconstant temperature vessel. When the needle penetrates into a sample toa depth of 1 mm, the temperature is measured.

g. Solubility: The solubility of a powdery sample (not fabricated) inwater and acetone was measured at 25° C.

EXAMPLE 1

2 g of dextran having a weight average molecular weight of 60,000(n=370) was dissolved in 55 ml. of water, and then 30 ml. of methylmethacrylate was added. With stirring, the air in the reaction vesselwas fully replaced with nitrogen gas. To the solution were added 0.06 gof cerric ammonium nitrate and 15 ml. of 0.1 N nitric acid, and themixture was reacted with stirring for 1 hour at 30° C. Then, 3.6 ml. ofa 1% aqueous solution of hydroquinone was added to stop the reaction.The reaction mixture was poured into methanol to form a precipitate. Theprecipitate was washed thoroughly with hot water, centrifuged, and driedat 50° C. under reduced pressure.

The crude dextran-methyl methacrylate copolymer so obtained was placedin a Soxhlet extractor, and extracted for 30 hours continuously usingacetone to afford 7.2 g of a purified dextran-methyl methacrylatecopolymer. The grafting rate was 456 %, and the degree of polymerizationof the poly (methyl methacrylate) in copolymer was 2,520.

The properties of the resulting product were compared with a cellulose(average molecular weight 30,000)/methyl methacrylate copolymer, asoluble starch (average molecular weight 100,000)/methyl methacrylatecopolymer and a dextran/acrylic acid copolymer, and the results areshown in Table 2.

                                      Table 2                                     __________________________________________________________________________                           Vicat      Water                                                  Tensile                                                                             Bending                                                                             softening                                                                           Contact                                                                            absorb-                                                strength                                                                            strength                                                                            point angle                                                                              tion  Solubility                                                                          Solubility                      Samples    (Kg/cm.sup.2)                                                                       (Kg/mm.sup.2)                                                                       (° C)                                                                        (°)                                                                         (%)   in water                                                                            in acetone                      __________________________________________________________________________    Dextran-methyl                                                                methacrylate copoly-                                                                     420   10.1  99    66   0.85  Insoluble                                                                           Insoluble                       mer of Example 1                                                              Cellulose-methyl                                                              methacrylate                                                                             290   8.0   138   71   0.11  Insoluble                                                                           Insoluble                       copolymer *1                                                                  Starch-methyl                                                                 methacrylate                                                                             250   2.4   124.5 70   0.37  Insoluble                                                                           Insoluble                       copolymer *2                                                                  Dextran-acrylic acid                                                          copolymer *3                                                                             --    --    --    --   dissolved                                                                           Soluble                                                                             Insoluble                       Dextran *4 --    --    --    --   dissolved                                                                           Soluble                                                                             Insoluble                       Poly(methyl                                                                   methacrylate) *5                                                                         500   8.8   92    72   0.22  Insoluble                                                                           Soluble                         __________________________________________________________________________     *1 grafting rate = 405%, m = 1400                                             *2 grafting rate = 470%, m = 8,000                                            *3 grafting rate = 25%, n = 370                                               *4 Material of Example 1, n = 370                                             *5 Sample isolated from the copolymer obtained in Example 1, m = 2520    

EXAMPLE 2

Examples 1 was repeated except that the starting dextran and thereaction conditions were varied as shown in Table 3 below. The yield,grafting rate, and the degree of polymerization of thepoly(methylmethacrylate) in the resulting copolymers are shown in Table3.

                                      Table 3                                     __________________________________________________________________________                      Amount                                                                             Amount                                                                   of   of   Amount                                                    Amount                                                                             Amount                                                                             methyl                                                                             cerium                                                                             of   Reaction       Graft-                           n of of   of   metha-                                                                             ammonian                                                                           0.1N tempera-                                                                           Reaction  ing  m of                     Run                                                                              formula                                                                            dextran                                                                            water                                                                              crylate                                                                            nitrate                                                                            HNO  ture time Yield                                                                              rate formula                  No.                                                                              (1)  (g)  (ml.)                                                                              (ml.)                                                                              (g)  (ml.)                                                                              (° C.)                                                                      (hours)                                                                            (g)  (%)  (2)                      __________________________________________________________________________    1  370  2    55   7.5  0.19 15   60   3    2.4  110  1050                     2  370  2    55   14   0.15 15   30   1    7.8  680  8100                     3  370  2    55   30   0.15 15   30   2    15.5 1400 15500                    4   55  2    55   7.5  0.15 15   25   2    2.3  259   460                     5  1220 2    55   1.5  0.01 15   60   3    1.8  176  3300                     6  3700 2    55   25   0.10 15   30   1    8.5  640  70000                    __________________________________________________________________________

EXAMPLE 3

The dextran/methyl methacrylate copolymer obtained in Example 1 wasplaced in a stainless steel mold, and preheated for 6 minutes bymaintaining the inside temperature at 180° C. Then, the mold was pressedfor 1 minute at 100 Kg/cm² gauge using a hydraulic press (26 tons,product of Toho Press Co., Ltd.), and then the mold was gradually cooledby passing cold water. When the temperature of the mold reacted 50° C.,it was removed from the press, and opened.

The resulting plate was cut by a lathe rotating at a speed of 2,000 rpm.At the same rotating speed, the surface of the plate was renderedconcave and convex to give a predetermined curvature. Then, it wasfitted into a pit plate of a lens polishing machine, and polished at arotating speed of 80 rpm at the lower part and 10 rpm at the upper part.Finally, the side surfaces of the lens are subjected to a bevel machineto produce a contact lens.

What is claimed is:
 1. A contact lens consisting essentially of a graft copolymer composition which consists essentially of a dextran unit of the formula ##SPC3##wherein n is an integer of 5 to 150,000 and a poly(alkyl methacrylate) unit of the formula ##EQU3## wherein m is an integer of 50 to 20,000, R is an alkyl group having 1 to 4 carbons, and the ratio of formula (2) unit to formula (1) unit is 50 to 3000% by weight, with the proviso that the graft composition is water- and acetone- insoluble at 25° C., the composition having been heated to from about 170° to 230° C. under a pressure of about 50 to 150 kg/cm².
 2. The contact lens molded article of claim 1 wherein the temperature is about 180° C. and the pressure is about 100 Kg/cm².
 3. The contact lens molded article of claim 1 wherein the temperature is maintained for about six minutes, after which the pressure is applied for about one minute, while still maintaining the temperature.
 4. The contact lens molded article of claim 1 wherein the graft composition is a dextran/methyl methacrylate copolymer.
 5. An artificial cornea consisting essentially of a graft copolymer composition which consists essentially of a dextran unit of the formula ##SPC4##wherein n is an integer of 5 to 150,000 and a poly(alkyl methacrylate) unit of the formula ##STR2## wherein m is an integer of 50 to 20,000, R is an alkyl group having 1 to 4 carbons, and the ratio of formula (2) unit to formula (1) unit is 50 to 3000% by weight, with the proviso that the graft composition is water- and acetoneinsoluble at 25° C. 